The candidate presents a 5-year career development plan that seeks to advance our understanding of how the interaction between different cell survival and death mechanisms mediate the response of c-KIT dependent cancers to targeted therapy. The proto-oncogene c-KIT is dysregulated via activating mutations in a number of human cancers that are generally refractory to conventional therapy. While the clinical responses to targeted c- KIT inhibitors, such as imatinib, have been hugely satisfying to clinicians, for the majority of patients whose tumors have ultimately suffered fatal relapses the efficacy remains only a starting point. Accordingly, investigating and characterizing c-KIT mediated cell death and survival mechanisms in the response to imatinib will expand both our scientific knowledge of basic cellular pathways as well as translate into new therapeutic opportunities. The aim of this proposal is to investigate the effects of targeted c-KIT inhibition on autophagy and apoptosis, two fundamental cellular processes that regulate cell survival and death, and how the interaction between these two processes impacts c-KIT dependent cancer cell survival, death, and response to therapy. The specific aims are: 1) To investigate the importance of apoptosis in the response of c-KIT dependent cancers to imatinib therapy, 2) To investigate the importance of autophagy in the response of c-KIT dependent cancers to imatinib therapy, and 3) To investigate the role of BIM and FOXO3a in connecting apoptosis and autophagy in the response of c-KIT dependent cancers to targeted therapy. These aims address fundamental questions of cancer cell biology with the opportunity to immediately translate the results into new therapeutic approaches in the treatment of c-KIT dependent cancers as well as potentially other targeted cancer therapies. This research proposal is part of a structured plan of scientific, technical, clinical, and career development components. The research will performed under the guidance of Dr. David Williams at Children's Hospital Boston and within the Division of Pediatric Hematology/Oncology at Children's Hospital Boston/Dana Farber Cancer Institute, which has a distinguished record of training successful physician scientists. In addition, the candidate will continue to gain clinical acumen in pediatric oncology at Children's Hospital Boston that will also inspire and inform his laboratory research. This career development plan will build upon this candidate's prior research and clinical experiences and ensure that he continues to develop the essential expertise required to become a successful independent investigator with a focus on cancer biology and clinical pediatric oncologist. PUBLIC HEALTH RELEVANCE: The major focus in the development of new cancer therapies is to molecularly modulate or target proteins and pathways, such as the proto-oncogene c-KIT, which are uniquely aberrant in cancer cells in order to enhance therapeutic effectiveness while minimizing the side-effects associated with traditional cytotoxic chemotherapy. Only by fully defining the molecular underpinnings of the success and failures of such targeted therapies can we understand cancer progression, develop alternative and synergistic therapies, and improve the care of cancer patients. The written critiques and criteria scores of individual reviewers are provided in essentially unedited form in the "Critique" section below. Please note that these critiques and criteria scores were prepared prior to the meeting and may not have been revised subsequent to any discussions at the review meeting. The "Resume and Summary of Discussion" section above summarizes the final opinions of the committee.